Mature T-Cell and NK-Cell Neoplasm (BSH 2021, BSH 2011)
Intro
Mature or peripheral T-cell neoplasms are biologically and clinically varied
Result from clonal proliferation of post-thymic lymphocytes
Good prognosis = Anaplastic Lymphoma Kinase (ALK) positive anaplastic large cell (ALCL)
Most nodal and extra-nodal T-cell lymphomas however have 30% 5-year survival
Rare and lack phase 3 trial data due to low numbers.
WHO-HAEM5 CLASSIFICATION
Mature T-Cell and NK-Neoplasms
T-Prolymphocytic leukaemia
T-Large granular lymphocytic leukaemia
NK-Large granular lymphocytic leukaemia
Adult T-cell leukaemia/lymphoma (ATLL)
Sezary Syndrome
Aggressive NK-cell leukaemia
Anaplastic Large cell lymphoma
ALK+ anaplastic large cell lymphoma
ALK- anaplastic large cell lymhpoma
Breast implant-associated anaplastic large cell lymphoma
Nodal T-Follicular Helper (TFH) cell lymphoma
Nodal TFH cell lymphoma, angioimmunoblastic type
Nodal TFH cell lymphoma, follicular type
Nodal TFH cell lymphoma, NOS
Other peripheral T-cell lymphomas
Peripheral T-cell lymphoma, NOS
Several Other Categories (see link above)
Includes EBV associated, intestinal, hepatosplenic, primary cutaneous, precursor and tumour-like categories.
Epidemiology
10% of lymphoid malignancies
Incidence 1.7 / 100,000 / year
NK-Cell lymphomas more common in Asia and associated with EBV
Adult T-Cell leukaemia/lymphoma (ATL) associated with HTLV-1
Presentation & Diagnosis
Often present late with advanced stage, poor performance status and extra-nodal disease
Para-neoplastic features seen – eosinophilia, HLH, autoimmune processes
FBC, Biochem, LDH, B2M, CXR, CT, BM Biopsy
PET-CT staging (identifies additional sites of disease in 50% cases compared to CT)
Mature T-Cell Leukaemias
T-Prolymphocytic Leukaemia (T-PLL)
Post-Thymic T-cell malignancy
Rare. 2% of all small lymphocytic leukaemias
Median age at diagnosis: 61 years
Median OS: <2 years
Up to 30% pt have an indolent phase then clinically aggressive disease with WBC >100, serous effusions, skin infiltration, splenomegaly and lymphadenopathy
Immunophenotype
Mature T cell markers – CD2+, CD3 weak+, CD5+, CD7+ (Variable CD4 and CD8)
Cytogenetics & molecular
Complex kayotype & Chromosome 8 abnormalities common.
90% show TCL1A/B and MTCP1 re-arrangements.
Association with ataxia telangiectasia (ATM gene disruption (11q22.3))
Treatment
Watchful waiting of asymptomatic cases
1st line therapy: IV Alemtuzumab. Transplant in first remission.
PCP and shingles prophylaxis. CMV PCR monitoring
(Marsden Hospital Cohort – 125 pt. Rx’d with IV Campath. CR 50%, PR21%. Median OS 16 months. 5-yr OS 32% for transplanted patients (mix of allo and auto))
T/NK-Large Granular Lymphocytic Leukaemia (LGLL)
Persistent clonal expansion of large, granular T (80%) or NK cells
Median age of diagnosis: 66 years
Associated with AI disorders, e.g. rheumatoid arthritis
Indolent, median survival >10 years
Most patients develop severe neutropenia (soluble Fas ligand released from LGL’s induces neutrophil apoptosis). Also other cytopenias, hepatosplenomegaly.
Immunophenotype
CD3+, TCRαβ+, CD8+, CD16+, CD57+, CD94+, KIR+, CD56-
Molecular
STAT3 mutation in 30-40% (occurs as a 2o event in an already expanding clone)
Treatment
Treat if complications from cytopenias
1st line: Ciclosporin or low dose methotrexate + GCSF/Epo
Goal of Rx: Reducing or silencing clone will restore counts. Not necessary to eliminate it.
Adult T-Cell Leukaemia/Lymphoma (ATLL)
Caused by HTLV-1, which is epidemic in Japan, Africa, South America
Median age of diagnosis: 53 years
Subtypes – leukaemic, lymphoma, skin, chronic & smouldering
Median OS: 8-10 months for acute vs 2-4 years for indolent subtypes
Immunophenotype
CD3+, CD4+, CCR4+, CD25+, CD26- CD7-
Molecular
Mutations in genes relating to immune evasion - CTLA4::CD28, ICOS::CD28, REL, HLA-A/B, PD-L1
STAT3 mutations more common in indolent presentations
Treatment - General
Screen 1st degree relatives & partners for HTLV-1 due to their increased risk
Check for strongyloides at diagnosis
Prophylaxis against opportunistic infection
Consider all patients for early allograft in first CR
1st line therapy - General
Nodal & acute disease - CHOP-based chemotherapy
Sking, smouldering & chronic - Zidovudine + Interferon-alfa
Mogamulizumab - Anti-CCR4 monoclonal Ab - most active in leukaemic disease
Aggressive NK-cell leukaemia
More common in Asia and almost always associated with EBV
Acute presentation with fever, jaundice, LNadenopathy, organomegaly
Patients are sick, may have DIC / HLH / MOF
Immunophenotype
CD3episilon+, CD56+, CD16+, CD2-, sCD3-, CD57-
Molecular
JAK/STAT and RAS/MAPK pathway mutations, TET2, KMT2D, CREBBP, PD-L1, PD-L2
OS 2 months
1st line: Clinical trial, ALL-type therapy
Nodal PTCL
Notes
BM involvement present in 35% of cases (PET-CT not very good at identifying this)
Outside BM, the nodal disease is almost always FDG-avid on PET-CT
Peripheral T-Cell Lymphoma, NOS (PTCL-NOS)
Largest group, 50% of T-cell cases
Includes ‘Follicular T-cell lymphoma’ and ‘Nodal peripheral T-cell lymphoma with a T-follicular helper (Tfh) phenotype’ which are new in the WHO 2016. Pathophysiology overlaps with AITL.
Aggressive, usually nodal
5-yr OS: 30%
1st line therapy:
Clinical trial, otherwise CHOP but disappointing results. ?Autograft in 1st CR.
Allograft data discussed in the guideline
Angio-Immunoblastic T Cell Lymphoma (AITL)
A disease of the elderly
Presentation often mimics an infectious process
Sometimes spontaneously regresses
Pathophysiology overlaps with PTCL-NOS
Molecular
TET2, DMNT3A, RHOA and IDH2 mutations
5-yr OS: 30%
1st line therapy: Trial, otherwise CHOP. ?Autograft in 1st CR.
Anaplastic Large Cell Lymphoma (ALCL)
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, usually only found in CNS.
NPM1-ALK fusion gene defines ALK+ ALCL
ALK+ significantly better prognosis than ALK-. Though ALK- still better than PTCL-NOS
Four subtypes
1o systemic ALK+, 1o systemic ALK-, 1o cutaneous and breast-implant associated
Different pathophys and different clinical responses
Median age of diagnosis: ALK+ 30 years, ALK- 55 years
Typically present at advanced stage with B symptoms
Treatment: advanced stage ALCL:
Clinical trial
or Brentuximab-CHP (Syn. A-CHP / BV-CHP) (Echelon-2 Trial, NICE approved Aug 2020)
?First remission autograft, data inconclusive
Relapse: Can re-treat with brentuximab
Treatment: Breast implant-associated ALCL
Surgical resection may be curative
Treatment: Cutaneous ALCL
Local excision +/- radiotherapy
Extra-Nodal PTCL
Extranodal NK/T-Cell Lymphoma (ENKTL)
Aggressive, EBV+
More common in East Asia and S. America
Median age at diagnosis: 50-60 years
Classically presents in nasal structure but nodal or BM involvement can be present
E.g.Presents as adult male with facial oedema, nasal obstruction and epistaxis
5-yr OS: 56% nasal, 34% extra-nasal
Prognostic score: PINK
Immunophenotype
NK phenotype: CD2+, CD56+, CD3epislon+ (and CD8+ variants)
Treatment:
Clinical Trial
Localised: Radiotherapy + Chemotherapy (e.g. GELOX, LVDP, DeVIC)
Advanced Stage: DDGP, SMILE (high toxicity). HSCT in 1st CR
Aggresive NK-Cell Leukaemia (ANKL)
Very rare. More prevalent in Asian countries
Median age of diagnosis: 40 years
DIC, HLH, Mulit-organ failure present at diagnosis
Median OS: 36 days without allograft, 266 days with allograft
Aggressive Intestinal T-Cell Lymphoma
Aggressive, ulcerating large cell tumours of the small bowel
Diarrhoea, Abdo pain, Weight loss
Median age at diagnosis: 62 years
Enteropathy associated T-cell lymphoma (EATL)
Almost always associated with (HLA)-DQ2 or (HLA)-DQ8, and coeliac disease
alpha-betaTCR+, CD30+, CD4-, CD8-, CD56-
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
Formerly known as EATL type II
Not associated with coeliac. More common in Asian and Hispanic countries
gamma-deltaTCR+, CD8+, CD56+
Median OS: 7 months
Treatment
MDT with gastro and nutrition teams
Clinical trial
1st line therapy: No satisfactory treatment. CHOP + Autograft
Treatment can be intensified with NCRI/SNLG protocol
Hepatosplenic T-Cell Lymphoma (HSTL)
Aggressive disease. Used to be considered disease of young age but wider spread now reported
Associated with post solid organ transplant or immunosuppression
BM biopsy morphology often mimics myelodysplasia
Often 7q abnormality
Historical median OS: 16 months
Treatment
Intensive chemo (IVE/ICE) followed by allograft in 1st CR
Subcutaneous pannciulitis-like T-Cell Lymphoma (SPTCL)
Presents as subcutaneous tumour nodules at any age.
Not universally aggressive. Consider CHOP / radiotherapy
a few trial notes
ECHELON-2 2018
600 patients, Phase 3, placebo-controlled
Brentuximab + CHP (A-CHP) vs CHOP
Most patients had anaplastic large cell lymphoma (but any CD30+ peripheral T-cell eligible)
Median PFS 48 months for A-CHP vs 20 months for CHOP
OS advantage